Standard therapeutic options for patients with squamous cell carcinoma of the head and neck (SCCHN) are often inadequate. Evaluation of the response to treatment is further complicated by the inability of traditional anatomic imaging modalities alone to distinguish radiation-induced and/or post-surgical changes from persistent cancer. Innovative approaches are required to improve the survival rates of SCCHN patients. The epidermal growth factor receptor (EGFR) is upregulated in SCCHN tumors, where the level of EGFR expression predicts disease-free and overall survival. Cumulative evidence supports the efficacy of therapies aimed at blocking EGFR. We have developed novel strategies to target EGFR and its mitogenic signaling pathway mediated by activation of Signal Transducer and Activator of Transcription 3 (Stat3) in SCCHN. Preliminary results suggest that positron emission tomography (PET) can accurately assess the response to EGFR antisense gene therapy. Additional investigation indicated that PET scanning with a proliferation marker, such as 3'-[18F] fluoro-3'- deoxythymidine (FLT), may be more accurate than PET imaging with a metabolic marker, such as 2-[18F] fluoro-2-deosyglucose (FDG). Using head and neck cancer xenograft models, we propose to determine which radiotracer is most useful for monitoring two different therapies to block EGFR mitogenic signaling by correlating the imaging results using FDG with FLT with: 1) ex vivo measures of signal transduction; and 2) tumor size alterations.